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J. Biol. Chem., Vol. 278, Issue 8, 5828-5836, February 21, 2003
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From the Activation of peroxisome
proliferator-activated receptors (PPARs) can regulate brain physiology
and provide protection in models of neurological disease; however,
neither their exact targets nor mechanisms of action in brain are
known. In many cells, PPAR
Peroxisome Proliferator-activated Receptor
Thiazolidinedione Agonists Increase Glucose Metabolism in
Astrocytes*
§¶,,
,,,, and
Department of Anesthesiology, University of
Illinois, Chicago, Illinois, 60612, Veterans Affairs
Chicago Health Care System West Side Division, Chicago, Illinois,
60680, ** Departmento de Bioquimica y Biologia Molecular,
Universidad de Salamanca, Salamanca 37007, Spain, and
§ Institute of Pharmacology, Catholic University Medical
School, Rome 00168, Italy
agonists increase glucose uptake and
metabolism. Because astrocytes store glucose and provide lactate to
neurons on demand, we tested effects of PPAR agonists on astroglial
glucose metabolism. Incubation of cortical astrocytes with the PPAR
thiazolidinedione (TZD) agonist pioglitazone (Pio) significantly
increased glucose consumption in a time- and dose-dependent
manner, with maximal increase of 36% observed after 4 h in 30 µM Pio. Pio increased 2-deoxy-glucose uptake
because of increased flux through the type 1 glucose
transporter. However, at this time point Pio did not increase
type 1 glucose transporter expression, nor were its effects blocked by
transcriptional or translational inhibitors. Pio also increased
astrocyte lactate production as soon as 3 h after incubation.
These effects were replicated by other TZDs; however, the order of
efficacy (troglitazone > pioglitazone > rosiglitazone)
suggests that effects were not mediated via PPAR activation. TZDs
increased astrocyte cAMP levels, and their glucose modifying effects
were reduced by protein kinase A inhibitors. TZDs inhibited state III
respiration in isolated brain mitochondria, whereas in astrocytes they
caused mitochondrial membrane hyperpolarization. Pio protected
astrocytes against hypoglycemia-induced cell death. Finally, glucose
uptake was modified in brain sections prepared from Pio-fed rats. These
results demonstrate that TZDs modify astrocyte metabolism and
mitochondrial function, which could be beneficial in neurological
conditions where glucose availability is reduced.
*
This work was supported in part by grants from the National
Multiple Sclerosis Society, Takeda Pharmaceuticals North America, and
GlaxoSmithKline.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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